Review Article

Platelet-rich Plasma in
Orthopaedic Applications:
Evidence-based
Recommendations for Treatment

Abstract
Wellington K. Hsu, MD Autologous platelet-rich plasma (PRP) therapies have seen a
Allan Mishra, MD dramatic increase in breadth and frequency of use for orthopaedic
conditions in the past 5 years. Rich in many growth factors that
Scott R. Rodeo, MD
have important implications in healing, PRP can potentially
Freddie Fu, MD
regenerate tissue via multiple mechanisms. Proposed clinical and
Michael A. Terry, MD surgical applications include spinal fusion, chondropathy, knee
Pietro Randelli, MD osteoarthritis, tendinopathy, acute and chronic soft-tissue injuries,
S. Terry Canale, MD enhancement of healing after ligament reconstruction, and muscle
strains. However, for many conditions, there is limited reliable
Frank B. Kelly, MD
clinical evidence to guide the use of PRP. Furthermore,
classification systems and identification of differences among
products are needed to understand the implications of variability.

JAAOS Plus Webinar

T he healthcare environment is
changing rapidly, and recently
there has been increased use of
Pathophysiology

Join Dr. Hsu, Dr. Rodeo, and Dr. Fu

for the JAAOS interactive webinar
discussing “Platelet-rich Plasma in
Orthopaedic Applications: Evidence-
based Recommendations for
Treatment,” on Tuesday, December
10, at 9 PM Eastern. The moderator
will be William N. Levine, MD, the
Journal’s Deputy Editor for Upper
Extremity topics.
To join and to submit questions in
advance, please visit the
OrthoPortal website: http://
orthoportal.aaos.org/jaaos/
J Am Acad Orthop Surg 2013;21:
739-748
http://dx.doi.org/10.5435/
JAAOS-21-12-739
Copyright 2013 by the American
Academy of Orthopaedic Surgeons.
platelet-rich plasma (PRP) in ortho-
paedic applications. However, sur-
geons often have little guidance with
regard to its indications and cost-
effectiveness. The continuous call for
data in the orthopaedic community
has led to a higher quantity and
quality of studies reporting the use of
PRP. In February 2011, the Ameri-
can Academy of Orthopaedic Sur-
geons hosted a forum involving ex-
pert clinicians and scientists in the
field of PRP therapy who presented
the best available level I through III
clinical studies reporting on the use
of PRP in the treatment of orthopae-
dic conditions.1 In this article, we ex-
amine several level I studies,2-16 level
II studies,17-24 and level III studies25-30
on the use of PRP in the treatment of
orthopaedic conditions.
Since 1950, PRP has been used to
manage dermatologic and oromaxil-
lofacial conditions.31,32 More re-
cently, interest has grown exponen-
tially in the potential use of PRP in
orthopaedic applications such as
bone formation and soft-tissue in-
jury, and as an adjunct in surgical re-
construction procedures.
PRP is defined as “a sample of au-
tologous blood with concentrations
of platelets above baseline values.”33
It is created through a two-phase
centrifugation process called plasma-
pheresis, in which liquid and solid
components of anticoagulated blood
are separated. The first phase con-
sists of an initial soft spin (1,200 to
1,500 RPM) with a relatively low
gravitational force in which plasma
and platelets are separated from red
blood cells and white blood cells

December 2013, Vol 21, No 12 739

Platelet-rich Plasma in Orthopaedic Applications: Evidence-based Recommendations for Treatment

Figure 1 platelet-rich and platelet-poor cial in conditions that require tissue

Illustration demonstrating
separation of the red blood cells
(RBCs) and white blood cells
(WBCs) from the platelet-rich
plasma (plasma and platelets)
following the two-step
centrifugation process.
(WBCs). The second phase, or hard
spin (4,000 to 7,000 RPM), is per-
formed to further concentrate the
plasma components (Figure 1). The
necessity of this phase is controver-
sial, as some commercial formula-
tions do not implement this process.
Furthermore, it is unclear what po-
tential benefits platelet-poor plasma
may have on tissue healing.34
In addition to platelets, PRP con-
tains other cell types with potentially
beneficial effects in tissue healing.
WBCs such as monocytes and poly-
morphonuclear neutrophils may trig-
ger a localized inflammatory effect.
Although some investigators believe
that this inflammatory effect is criti-
cal to the tissue repair process, neu-
trophils have been hypothesized to
impede healing.35 The inclusion of
WBCs in the PRP preparation varies
depending on the particular indica-
tion.
Proteins such as platelet-derived
growth factor (PDGF), vascular en-
dothelial growth factor, endothelial
cell growth factor, and basic fibro-
blast growth factor can be detected
at high concentrations in PRP; conse-
quently, many investigators have
postulated that PRP may be benefi-
healing.33,36 In fact, Wasterlain et al36
recently demonstrated that local in-
tratendinous injection of PRP can
lead to a systemic ergogenic effect,
temporarily increasing serum levels
of insulin-like growth factor–1, vas-
cular endothelial growth factor, and
basic fibroblast growth factor. Con-
versely, other proteins present in PRP
have demonstrated inhibitory effects,
such as transforming growth factor
(TGF)-β1, which may lead to vari-
able clinical results in certain appli-
cations.37
The exact role of thrombin in PRP
has been debated. Thrombin and/or
calcium chloride is necessary to cata-
lyze the conversion of fibrinogen to
fibrin, but it also induces platelets to
secrete growth factors. Some data,
however, suggest that exogenous
thrombin activation of PRP may ac-
tually diminish its ability to induce
bone formation compared with non–
thrombin-activated PRP.38
More than 40 commercial systems
exist that claim to concentrate whole
blood into a platelet-rich substance.
However, many factors contribute to

From the Department of Orthopaedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL (Dr. Hsu and
Dr. Terry), the Department of Orthopaedic Surgery, Stanford University Medical Center, Stanford, CA (Dr. Mishra), the Department of
Orthopaedic Surgery and the Research Department, Hospital for Special Surgery, New York, NY (Dr. Rodeo), the Department of
Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA (Dr. Fu), the Department of Orthopaedic Surgery, University of Milan,
Milan, Italy (Dr. Randelli), the Department of Orthopaedic Surgery, University of Tennessee–Campbell Clinic, Memphis, TN
(Dr. Canale), and Forsyth Street Orthopaedics, Macon, GA (Dr. Kelly).
Dr. Hsu or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of Graftys,
Medtronic Sofamor Danek, Pioneer Surgical, Stryker, Terumo Medical, and Zimmer; has received research or institutional support
from Baxter, Medtronic Sofamor Danek, and Pioneer Surgical; and serves as a board member, owner, officer, or committee member
of the American Academy of Orthopaedic Surgeons (AAOS), the Lumbar Spine Research Society, and the North American Spine
Society. Dr. Mishra or an immediate family member has received royalties from Biomet and ThermoGenesis, is an employee of
BioParadox, and has stock or stock options held in BioParadox and ThermoGenesis. Dr. Rodeo or an immediate family member
serves as a paid consultant to Smith & Nephew and has stock or stock options held in Cayenne Medical. Dr. Fu or an immediate
family member has received royalties from ArthroCare; is an employee of and has stock or stock options held in Stryker; and serves
as a board member, owner, officer, or committee member of the AAOS, the American Orthopaedic Society for Sports Medicine, the
Orthopaedic Research and Education Foundation (OREF), and the International Society of Arthroscopy, Knee Surgery, and
Orthopaedic Sports Medicine. Dr. Terry or an immediate family member has received royalties from, serves as a paid consultant to,
has received research or institutional support from, and has received nonincome support (such as equipment or services),
commercially derived honoraria, or other non-research–related funding (such as paid travel) from Smith & Nephew. Dr. Randelli or an
immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of and has received
research or institutional support from Biomet; serves as a paid consultant to DePuy; and serves as a board member, owner, officer,
or committee member of the European Society of Sports Traumatology, Knee Surgery & Arthroscopy. Dr. Canale or an immediate
family member serves as a board member, owner, officer, or committee member of the AAOS, Bioworks, the Campbell Foundation,
and OREF. Dr. Kelly or an immediate family member serves as a board member, owner, officer, or committee member of OREF and
the Twentieth Century Orthopaedic Association.

740 Journal of the American Academy of Orthopaedic Surgeons


Table 1
Common Platelet-rich Plasma Formulations
System
Cascade (Musculoskeletal
Transplant Foundation)39
GPS III (Biomet)39
Magellan (Arteriocyte Medical
Systems)39
ACP (Arthrex)40,41
SmartPReP (Harvest Technolo-
gies)42
Symphony II (DePuy)43
P-LRP = platelet-leukocyte-rich plasma, P-PRF = pure platelet-rich fibrin, P-PRP = pure platelet-rich plasma
the variable content and, subse-
quently, to the performance of PRP
from different preparation methods
(Table 1). First, the final platelet con-
centration varies not only between
techniques but also within a given
technique.39,44-46 The final platelet
concentration of any PRP product
depends on the initial volume of
whole blood, the platelet recovery ef-
ficiency of the chosen technique, the
final volume of plasma used to sus-
pend concentrated platelets, the rela-
tive concentration of WBCs and/or
red blood cells, and the concomitant
use of thrombin. Furthermore, indi-
vidual patient factors such as comor-
bidities, age, and circulation lead to
differences in growth factor and cell
content.45
A higher concentration or absolute
number of platelets within PRP does
not necessarily lead to an enhanced
tissue healing effect. In fact, Giusti
et al47 proposed that the most effica-
cious platelet concentration for tissue
healing is 1.5 × 106 platelets per mi-
croliter. In addition, the dose-
response curve is not linear, and a
saturation effect has been described
in which an inhibitory cascade en-
sues once a sufficiently high concen-
tration of platelets is reached. Be-
cause platelets can exert the greatest
influence on healing during or imme-
diately after the inflammatory phase
December 2013, Vol 21, No 12
Wellington K. Hsu, MD, et al
Type Whole Blood Volume (mL) Centrifuge Time (min)
P-PRF 18 6
P-LRP 55 15
P-LRP 26 17
P-PRP 10 5
P-LRP 60 16
P-LRP 54 5
Table 2
Sports Medicine Platelet-rich Plasma Classification System
PRP Typea White Blood Cells (WBCs) Activated?
1 Increased over baseline No
2 Increased over baseline Yes
3 Minimal or no WBC No
4 Minimal or no WBC Yes
PRP = platelet-rich plasma
a
Any PRP type can have an associated subtype A or subtype B. Subtype A has ≥5 times
the concentration of platelets in the final preparation compared to baseline. Subtype B has
<5 times the concentration of platelets in the final preparation compared to baseline.
Adapted with permission from Mishra A, Harmon K, Woodall J, Vieira A: Sports medicine
applications of platelet rich plasma. Curr Pharm Biotechnol 2012;13(7):1185-1195.
of injury, some authors have postu-
lated that the timing of the adminis- Bone Healing
tration of PRP has a greater impact
PRP has demonstrated osteogenic
on healing than does the number of
properties in several in vitro and pre-
platelets.22
clinical studies;49,50 however, clinical
The absence of a validated classifi-
reports have not been as promising.
cation system that identifies crucial
differences between PRP formula- In a prospective observational study
tions makes it difficult to compare involving 123 foot and ankle fusions
studies. In an attempt to standardize in 62 patients with risk factors for
different PRP systems, both DeLong nonunion, autologous platelet con-
et al35 and Mishra et al48 have pro- centrate (APC) was used in 67 proce-
posed systems that classify PRP sys- dures, and APC and bone graft were
tems by activation mechanism, plate- used in 56 procedures.17 Because the
let number, and/or cell content. 6% nonunion rate for all patients
Although the systems have yet to be was below historical outcomes, the
validated in the literature, they repre- authors concluded that APC might
sent an important step in furthering be beneficial in this patient popula-
this area of research (Table 2). tion. However, these patients under-
741
Platelet-rich Plasma in Orthopaedic Applications: Evidence-based Recommendations for Treatment
went a variety of procedures (ankle,
hindfoot, midfoot, and forefoot sur-
gery), and the type of bone graft
used (ie, allograft, autograft) varied
based on surgeon choice.
In a level III prospective study, Tsai
et al25 reported lumbar posterolateral
spine fusion rates with local bone
graft in 67 consecutive patients, 34
of whom were treated with addi-
tional platelet glue. At 2-year follow-
up, there was no difference in non-
union rate (15%, platelet glue; 10%,
control group) as determined on
flexion-extension radiographs and
fine-cut CT scans. Similarly, in a ret-
rospective cohort study of 76 consec-
utive patients who underwent pos-
terolateral lumbar fusion, the
nonunion rates at clinical follow-up
of ≥24 months did not differ signifi-
cantly between iliac crest bone graft
plus platelet-gel preparation com-
pared with autologous bone graft
alone (25% and 17%, respectively; P
= 0.18).26 Weiner and Walker27 dem-
onstrated a significantly lower fusion
rate with the use of autologous
growth factors from PRP and au-
tograft in single-level posterolateral
lumbar fusion compared with iliac
crest bone graft alone (62% and
91%, respectively; P < 0.05). The ad-
dition of PRP to autograft for pos-
terolateral and interbody spine fu-
sion does not appear to confer any
benefit in fusion rates and, in fact, it
may be detrimental.
Currently, limited clinical evidence
exists demonstrating any beneficial
effects from the use of PRP in bone
healing applications. The available
evidence indicates that PRP is not ef-
ficacious either alone or as an ad-
junct to local bone graft in these ap-
plications.
Cartilage Healing
PRP contains factors that have been
shown to be critical in joint repair,
742
such as TGF-β1, thrombospondin-1,
and insulin-like growth factor.51
Consequently, its use has been pro-
posed in patients with symptomatic
cartilage defects or osteochondral le-
sions.
In a level I study in which 78 pa-
tients with bilateral knee osteoarthri-
tis were randomized to receive a sin-
gle WBC-filtered PRP injection, two
PRP injections 3 weeks apart, or a
single saline injection, both PRP
groups were found to have signifi-
cantly better outcomes than the con-
trol group 6 months after treatment.2
In a separate level I randomized con-
trolled trial (RCT) in 120 patients,
Cerza et al3 reported significantly
better clinical outcomes up to 24
weeks after a local injection of PRP
compared with injection of hy-
aluronic acid (P < 0.001). Con-
versely, in an RCT of 109 patients,
Filardo et al4 demonstrated that al-
though intra-articular PRP injections
can offer significant clinical improve-
ment up to 1 year after treatment,
these results were not better com-
pared with hyaluronic acid injec-
tions. Furthermore, the authors of a
Clinical Practice Guideline spon-
sored by the American Academy of
Orthopaedic Surgeons were “unable
to recommend for or against growth
factor injections and/or platelet rich
plasma for patients with symptom-
atic OA of the knee.”52
One case-control clinical study has
been published to date on the man-
agement of cartilage defects with
PRP.18 In this level II study, 32 pa-
tients with symptomatic osteochon-
dral lesions of the talus classified on
CT scan using the Ferkel system
were randomized to receive intra-
articular injections of either hy-
aluronic acid or PRP. At 28-week
follow-up, patients who received
PRP demonstrated significantly
greater improvements in pain, stiff-
ness, and function scores compared
with those treated with hyaluronic
Journal of the American Academy of Orthopaedic Surgeons
acid (P < 0.0001). Eighty-seven per-
cent of patients enrolled in the PRP
group obtained good results, which
led these authors to conclude that
PRP should be considered as a first-
line treatment of symptomatic osteo-
chondral lesions of the talus. Al-
though preliminary evidence exists,
further study is required before con-
clusions can be made regarding the
efficacy of PRP in the management
of osteochondral lesions and knee
osteoarthritis.
Chronic Tendinopathy
Elbow epicondylitis, which is charac-
terized by failure of the normal ten-
don repair mechanism, is a common
malady that leads to chronic pain
and decreased function in activities
of daily living. Although treatment
recommendations range from brac-
ing, physiotherapy, and steroid injec-
tions to arthroscopic or open dé-
bridement, some investigators have
indicated that the local delivery of
humoral mediators may enhance ten-
don healing and lead to improved
clinical outcomes.
In a controlled trial comparing lo-
cal injection of either PRP formula-
tion containing WBCs or bupiva-
caine in 20 patients with chronic
elbow epicondylar tendinosis,
19
Mishra and Pavelko demonstrated
significant improvement in clinical
outcomes in visual analog scale
(VAS) and Mayo elbow scores at 8
weeks after treatment with PRP (P =
0.001 and P = 0.008, respectively).
Patients treated with PRP had a 93%
reduction in pain compared with
baseline at an average follow-up of
25.6 months (P < 0.0001). Thanasas
et al5 compared clinical outcomes in
28 patients with the same condition
who were randomized to local injec-
tion of either autologous whole
blood or PRP in a level I study. Al-
though VAS score improvements

were reported at every follow-up in-
terval up to 6 months in the PRP
group, the only statistically signifi-
cant difference was seen at the
6-week time point.
Using the same methodology as did
Mishra and Pavelko,19 a different
group of researchers compared local
injection of PRP with corticosteroid
for lateral epicondylitis in a level I
study of 100 patients; they published
one article reporting on the 1-year
follow-up results7 and a second arti-
cle on the 2-year follow-up results.6
Significantly greater reduction in
VAS scores was achieved with PRP
measured at each time point up to 24
months after injection (P < 0.0001).
Comparison of outcomes at 1- and
2-year follow-up demonstrated that
clinical scores in the corticosteroid
group steadily declined, whereas
those of the PRP group were main-
tained.6 These studies suggest that
PRP formulations containing WBCs
improve patient outcomes compared
with local injection of anesthetic,
whole blood, or corticosteroid.
The results have not been as prom-
ising for other tendinopathies. In a
level I RCT comparing local injec-
tion of PRP to saline for Achilles ten-
dinopathy in conjunction with eccen-
tric exercises, de Vos et al8 reported
no difference in the improvement of
clinical outcome up to a 24-week
follow-up. In a follow-up study,
members of the same research group
randomized 54 patients diagnosed
with chronic Achilles tendinopathy
to blinded injections containing ei-
ther PRP or saline in addition to a
training program.9 Although patients
in both groups had improved clinical
outcomes 1 year after injection, there
was no significant difference in bene-
fit. In a prospective level III study, Fi-
lardo et al28 studied the utility of
PRP injection for refractory jumper’s
knee in 31 patients who were treated
with either local injection of PRP or
exercise. At 6-month follow-up, pa-
December 2013, Vol 21, No 12
tients who received PRP demon-
strated a greater activity level; how-
ever, all other outcome measures,
including VAS and pain level evalua-
tion, did not differ significantly from
the control group. Gosens et al10
demonstrated that, for patients pre-
viously treated with cortisone,
ethoxysclerol, and/or surgery for pa-
tellar tendinopathy, PRP did not con-
fer as much improvement in VAS
scores as it did in patients who had
had no prior intervention.
Although the cost-effectiveness of
treatment is unclear, the clinical evi-
dence suggests that local injection of
PRP containing WBCs may be bene-
ficial to patients with chronic elbow
epicondylitis refractory to standard
nonsurgical treatment. However, the
results of PRP treatment of other
chronic tendinopathies are not as
clear.
Surgical Repair of Acute
Soft-tissue Injuries
Because of the rich source of growth
factors in PRP, it has been suggested
that administering PRP in the setting
of acute soft-tissue injuries could
provide enhanced healing, thus facil-
itating an early return to sports.20,29
Tendon healing is typically character-
ized by an initial inflammatory re-
sponse that is associated with the in-
flux of factors such as PDGF and
TGF-β (within 2 days), resulting in
angiogenesis (2 to 3 days), and colla-
gen synthesis (3 to 5 days).53 Because
PRP contains these critical growth
factors that can aid in the inflamma-
tory response, its utility may be
greatest when administered early in
the healing period.54
Anterior Cruciate Ligament
Reconstruction
Anterior cruciate ligament (ACL) re-
construction has traditionally been
considered a successful procedure
Wellington K. Hsu, MD, et al
with excellent long-term results and
patient satisfaction. Maturation of
the tendon graft is necessary for opti-
mal biomechanical strength and re-
turn to activity. Graft remodeling
may be accelerated by the actions of
PDGF, TGF-β1, and insulin-like
growth factor–1.29 The intra-
articular biologic environment pre-
sents challenges to tissue healing that
may lead to suboptimal results. For
example, this anatomic area is not
only poorly vascularized but also
produces synovial fluid containing
proteases that prevent fibrin clot for-
mation, which is normally required
for initial wound healing.55 Further-
more, this contained milieu may not
deliver important growth factors for
healing.
In vitro studies have demonstrated
the ability of PRP to improve ACL
cell viability and function.43 Thus,
treatments have been proposed to in-
crease both histologic metrics in re-
pair and remodeling at the midsub-
stance of the reconstructed ACL as
well as within the patellar tendon
harvest site in patients treated with
bone–patellar tendon–bone au-
56
tografts. Early administration of
PRP during the inflammatory pro-
cess may lead to an accelerated heal-
ing cascade that is shorter than the
typical 1-year period expected for
full graft maturation.56
Radice et al29 conducted a prospec-
tive single-blind study of 50 patients
who were treated with either ACL
autograft alone or ACL autograft
with application of PRP gel at the
time of surgery. At 1-year follow-up,
it was found that application of PRP
gel resulted in significantly faster bi-
ologic maturation than did autograft
alone as measured on MRI (177 and
369 days, respectively; P < 0.001)
(Figure 2). Similarly, in an RCT with
108 patients, Orrego et al21 demon-
strated that the addition of platelet
concentrate to a semitendinosus-
gracilis graft and to the femoral tun-
743
Platelet-rich Plasma in Orthopaedic Applications: Evidence-based Recommendations for Treatment

Figure 2 platelet-enriched gel. In the investiga-

tional group, gel was sutured into
the allograft and applied in the tibial
tunnel. At a mean follow-up of 2
years and based on clinical and ra-
diographic outcomes according to
the International Knee Documenta-
tion Committee score, KT-1000 ar-
thrometer (MEDmetric), plain radi-
ography, and MRI, the authors
concluded that there were no signifi-
cant differences in any parameter.
The variability in clinical outcomes
could be attributed to several factors,
including PRP preparation/centri-
fugation, graft choice, rehabilitation
protocols, and application technique.
These findings were supported by
Magnussen et al,58 who demon-
Sagittal T2-weighted magnetic resonance images of the knee obtained 6 strated that the use of PRP in al-
months after anterior cruciate ligament reconstruction with bone–patellar lograft ACL reconstructions did not
tendon–bone graft without platelet-rich plasma (PRP) (A) and 5 months after lead to differences in patient-
reconstruction with PRP (B). A more homogeneous signal was demonstrated
in grafts with PRP, which suggests a quicker maturation rate. (Reproduced reported outcomes at 2-year follow-
with permission from Radice F, Yánez R, Gutiérrez V, Rosales J, Pinedo M, up.
Coda S: Comparison of magnetic resonance imaging findings in anterior More than 40% of patients who
cruciate ligament grafts with and without autologous platelet-derived growth
undergo ACL reconstruction with a
factors. Arthroscopy 2010;26[1]:50-57.)
single-bundle patellar tendon au-
tograft report residual symptoms (eg,
nel led to a significantly higher rate et al56 reported results in 37 patients pain, sensory problems) at the donor
of graft maturation 6 months after who had second-look arthroscopies site.59 In an RCT involving 40 pa-
reconstruction, signified by low- after ACL reconstruction with autog- tients, Cervellin et al12 studied the ef-
intensity signal on MRI (P = 0.036). enous hamstring grafts with and fect of the addition of autologous
In contrast, Silva and Sampaio20 ap- without injection of a PRP prepara- PRP gel sutured into the patellar and
plied PRP in the femoral tunnels in tion rich in growth factors. Both tibial bone plug harvest site. Al-
30 patients and found no difference gross morphology and histologic though VAS scores were not signifi-
in MRI findings of the signal inten- evaluation of graft biopsies demon- cantly different at 12-month follow-
sity of fibrous interzone in the tun- strated improvements in graft re- up, Victorian Institute of Sport
nels 3 months after surgery. The dif- modeling and the amount of new Assessment questionnaire scores,
ferences in this study20 may be connective tissue enveloping the which have been validated to quan-
partially explained by the shorter graft, as well as a higher graft thick- tify knee function in subjects with
time point of radiographic imaging ness and synovial coverage rating for patellar tendinopathy,60 were signifi-
and smaller number of patients than patients treated with PRP. Although cantly higher in patients treated with
in either of the other two studies.21,29 the period of time from index ACL PRP (P = 0.041), suggesting greater
A systematic review of eight con- surgery to second-look arthroscopy satisfaction with knee function. In a
trolled clinical trials concluded that varied widely, the authors concluded separate level I randomized study, 12
the addition of platelet concentrates that use of PRP in vivo may enhance patients who received 20 to 40 mL
to ACL reconstruction may have a the ligamentization process in ten- of PRP gel at the patellar tendon de-
20% to 30% beneficial effect on don grafts. fect were compared with 15 patients
graft maturation.57 In a level I study, Nin et al11 ran- who did not receive PRP.13 At
Histologic analysis of ACL grafts domized 100 patients with ACL re- 6-month follow-up MRI examina-
following PRP application also sug- construction with patellar tendon al- tion, the patellar tendon gap area
gests enhanced maturation. Sánchez lograft to receive or not receive was found to be significantly smaller

744 Journal of the American Academy of Orthopaedic Surgeons


in the PRP group (P = 0.046) (Figure
3). Furthermore, immediate postop-
erative VAS scores were lower in the
investigational group than in the
control group (P = 0.02). Based on
these findings, the authors concluded
that PRP can both enhance tendon
healing within the patellar tendon
defect and contribute anti-inflam-
matory effects that may modulate
pain after surgery.
Rotator Cuff Repair
Five level I and II controlled studies
have compared results after surgical
repair of rotator cuff injuries with
and without the adjunctive use of
PRP. Castricini et al14 reported no
significant difference in Constant
scores and tendon scores graded on
MRI up to 16 months after primary
arthroscopic rotator cuff repair with
or without the use of autologous
platelet-rich fibrin matrix (PRFM).
These authors concluded that PRP
had no demonstrable benefit for
small to medium-size rotator cuff
tears.
Similarly, in a level II study involv-
ing 79 patients in whom reattach-
ment of the rotator cuff was per-
formed with suture anchors, the
clinical scores in the group with
PRFM sutured in the tendon-bone
interface were no different from
those of the control group at a mini-
mum 1-year follow-up.22 In fact, lo-
gistic regression analysis of both
groups demonstrated that the use of
PRFM was a significant predictor of
tendon defect at 12-week follow-up
(P = 0.037), suggesting that it may
have a negative effect on healing.
The authors postulated that the vari-
ability in the composition and qual-
ity of PRP for each patient likely led
to variability in the capacity for ten-
don repair. In a prospective cohort
study involving 42 patients, Jo et al23
demonstrated that, compared with the
control group, application of PRP gel
December 2013, Vol 21, No 12
Wellington K. Hsu, MD, et al
Figure 3
Axial magnetic resonance images of the gap area (dotted line near the top of
panel A; arrow, panel B) of the patellar tendon harvest site in a patient who
did not receive platelet-rich plasma (PRP) (A) and a patient who did receive
PRP (B). The gap is smaller in panel B than in panel A. (Adapted with
permission from de Almeida AM, Demange MK, Sobrado MF, Rodrigues MB,
Pedrinelli A, Hernandez AJ: Patellar tendon healing with platelet-rich plasma:
A prospective randomized controlled trial. Am J Sports Med
2012;40[6]:1282-1288.)
to arthroscopic rotator cuff repairs did different from that used by Castricini
not accelerate recovery with respect to et al14 and Rodeo et al.22
pain, motion, strength, or overall pa- In a randomized trial involving 40
tient satisfaction at any time point up patients with subacromial decom-
to a minimum of 16 months postoper- pression, the use of PRP led to signif-
atively. The difference in re-tear rate icantly decreased pain scores and im-
between the groups at 9-month proved shoulder range of motion
follow-up was not statistically signifi- postoperatively compared with that
cant. of control patients (P < 0.001).16 De-
Conversely, in a double-blind RCT spite this, a systematic review per-
of 53 patients, intraoperative appli-
formed by Chahal et al61 concluded
cation of PRP with an autologous
that PRP does not have an effect on
thrombin component during arthro-
re-tear rates or clinical outcomes af-
scopic rotator cuff repair led to sig-
ter arthroscopic repair. Although
nificantly higher Constant and Uni-
there is some evidence demonstrating
versity of California, Los Angeles
potential benefit, further study is re-
scores and strength in external rota-
tion 3 months after surgery but not quired before the routine use of ad-
at 6, 12, and 24 months compared junctive PRP during shoulder surgery
with control subjects.15 In grade 1 can be recommended.
and 2 tears, the use of PRP led to sig-
nificantly higher strength in external Achilles Tendon Repair
rotation scores at 3, 6, 12, and 24 Achilles tendon ruptures can be asso-
months postoperatively (P < 0.05) ciated with prolonged recovery and
and a lower rate of re-rupture (P = postoperative complications such as
0.08). Notably, Randelli et al15 used re-rupture because of the poor vascu-
a commercial preparation of PRP lar environment surrounding the re-
745
Platelet-rich Plasma in Orthopaedic Applications: Evidence-based Recommendations for Treatment
pair. In a case-control study involv-
ing 12 athletes who had acute
Achilles tendon repair, patients who
were injected with a preparation rich
in growth factors around the tendon
fibers demonstrated significantly
faster recovery of range of motion (P
= 0.025) and time to running (P =
0.042).30 However, a level II study of
30 patients who underwent Achilles
tendon repair with or without PRP
administration demonstrated no sig-
nificant difference between the two
groups in heel raise index or elastic-
ity modulus at 1-year follow-up.24 In
fact, the Achilles Tendon Total Rup-
ture Score was lower in the PRP
group, which suggests that intraoper-
ative use of PRP may be detrimental.
Because the formulation of PRP used
in this study was 17 times that of
baseline platelets without WBCs, the
difference in preparations could have
contributed to the conflicting results.
Although no significant difference in
clinical outcomes has been found, pre-
liminary clinical evidence suggests that
PRP may be beneficial during the lig-
amentization and maturation processes
of graft healing as well as that of the
patellar tendon graft harvest sites in
ACL reconstruction. For rotator cuff
and Achilles tendon repairs, the results
of clinical studies are equivocal, and
further study is needed before definitive
conclusions can be drawn and recom-
mendations made.
Cost-benefit
Considerations
As the quality of investigational
studies regarding PRP increases, so
too will the demand for its clinical
use. The market for PRP, valued at
$45 million in 2009, is expected to
grow to $126 million by 2016.62
Although the body of evidence for
the use of PRP in orthopaedic condi-
tions is rapidly expanding, insuffi-
cient evidence exists to perform an
746
adequate cost-benefit analysis. PRP
therapy is not covered by many in-
surance plans in the United States,
and until appropriate data are avail-
able, this situation may not change.
In a study involving diabetic wound
ulcers, the cost of PRP treatment in
2006 was estimated to be $450 per
treatment, for a monthly cost of
$3,600 for an uncomplicated ulcer.63
Dougherty63 concluded that PRP gel
was more cost-effective than wet-to-
dry saline dressings in managing
nonhealing diabetic foot ulcers over
a 5-year period.
In the Netherlands, PRP treatment
costs approximately twice as much
as corticosteroid treatment but just
half that of surgical débridement.6
Although the short-term costs of
PRP are greater than those of stan-
dard steroid injections, if the inci-
dence of further intervention (ie, sur-
gery, re-injection) is decreased at
long-term follow-up or if satisfaction
is significantly greater with PRP, then
an overall cost savings can be real-
ized. Gosens et al6 suggested that
PRP may be less expensive than cor-
ticosteroids at 2-year follow-up in
the management of lateral epicondy-
litis.
In the orthopaedic literature, fu-
ture research with data from
EuroQol-5D measures would greatly
enhance the ability to implement a
cost-benefit analysis. More impor-
tantly, comparison groups would
have to be properly chosen in such a
study. Cost analysis would have to
be compared with a surgical inter-
vention. Proper economic evaluation
must take into account reported suc-
cess rates, timing of treatment, and
the patient population.
Summary
Although PRP has a theoretic benefit
in the augmentation of tissue heal-
ing, the evidence-based literature
Journal of the American Academy of Orthopaedic Surgeons
suggests that success varies depend-
ing on the preparation method and
composition, medical condition of
the patient, anatomic location, and
tissue type. In response to a growing
interest among both patients and sur-
geons in the use of PRP, recent stud-
ies have reported outcomes in a vari-
ety of conditions. Further critical
review and rigorous clinical studies
are required to formulate a cost-
effective, efficacious algorithm for
the use of PRP in patients with or-
thopaedic conditions.
References
Evidence-based Medicine: Levels of
evidence are described in the table of
contents. In this article, references
2-16 are level I studies. References
17-24 are level II studies. References
25-30 are level III studies.
References printed in bold type are
those published within the past 5
years.
1. PRP an Unproven Option, Say Experts.
Available at: http://www.aaos.org/news/
acadnews/2011/AAOS1_2_16.asp.
Accessed September 23, 2013.
2. Patel S, Dhillon MS, Aggarwal S,
Marwaha N, Jain A: Treatment with
platelet-rich plasma is more effective
than placebo for knee osteoarthritis: A
prospective, double-blind, randomized
trial. Am J Sports Med 2013;41(2):356-
364.
3. Cerza F, Carnì S, Carcangiu A, et al:
Comparison between hyaluronic acid
and platelet-rich plasma, intra-articular
infiltration in the treatment of
gonarthrosis. Am J Sports Med 2012;
40(12):2822-2827.
4. Filardo G, Kon E, Di Martino A, et al:
Platelet-rich plasma vs hyaluronic acid to
treat knee degenerative pathology: Study
design and preliminary results of a
randomized controlled trial. BMC
Musculoskelet Disord 2012;13:229.
5. Thanasas C, Papadimitriou G,
Charalambidis C, Paraskevopoulos I,
Papanikolaou A: Platelet-rich plasma
versus autologous whole blood for the
treatment of chronic lateral elbow
epicondylitis: A randomized controlled
clinical trial. Am J Sports Med 2011;
39(10):2130-2134.

6. Gosens T, Peerbooms JC, van Laar W,
den Oudsten BL: Ongoing positive effect
of platelet-rich plasma versus
corticosteroid injection in lateral
epicondylitis: A double-blind
randomized controlled trial with 2-year
follow-up. Am J Sports Med 2011;39(6):
1200-1208.
7. Peerbooms JC, Sluimer J, Bruijn DJ,
Gosens T: Positive effect of an
autologous platelet concentrate in lateral
epicondylitis in a double-blind
randomized controlled trial: Platelet-rich
plasma versus corticosteroid injection
with a 1-year follow-up. Am J Sports
Med 2010;38(2):255-262.
8. de Vos RJ, Weir A, van Schie HT, et al:
Platelet-rich plasma injection for chronic
Achilles tendinopathy: A randomized
controlled trial. JAMA 2010;303(2):144-
149.
9. de Jonge S, de Vos RJ, Weir A, et al:
One-year follow-up of platelet-rich
plasma treatment in chronic Achilles
tendinopathy: A double-blind
randomized placebo-controlled trial. Am
J Sports Med 2011;39(8):1623-1629.
10. Gosens T, Den Oudsten BL, Fievez E,
van ‘t Spijker P, Fievez A: Pain and
activity levels before and after platelet-
rich plasma injection treatment of
patellar tendinopathy: A prospective
cohort study and the influence of
previous treatments. Int Orthop 2012;
36(9):1941-1946.
11. Nin JR, Gasque GM, Azcárate AV, Beola
JD, Gonzalez MH: Has platelet-rich
plasma any role in anterior cruciate
ligament allograft healing? Arthroscopy
2009;25(11):1206-1213.
12. Cervellin M, de Girolamo L, Bait C,
Denti M, Volpi P: Autologous platelet-
rich plasma gel to reduce donor-site
morbidity after patellar tendon graft
harvesting for anterior cruciate ligament
reconstruction: A randomized, controlled
clinical study. Knee Surg Sports
Traumatol Arthrosc 2012;20(1):114-
120.
13. de Almeida AM, Demange MK, Sobrado
MF, Rodrigues MB, Pedrinelli A,
Hernandez AJ: Patellar tendon healing
with platelet-rich plasma: A prospective
randomized controlled trial. Am J Sports
Med 2012;40(6):1282-1288.
14. Castricini R, Longo UG, De Benedetto
M, et al: Platelet-rich plasma
augmentation for arthroscopic rotator
cuff repair: A randomized controlled
trial. Am J Sports Med 2011;39(2):258-
265.
15. Randelli P, Arrigoni P, Ragone V,
Aliprandi A, Cabitza P: Platelet rich
plasma in arthroscopic rotator cuff
repair: A prospective RCT study, 2-year
follow-up. J Shoulder Elbow Surg 2011;
20(4):518-528.
December 2013, Vol 21, No 12
16. Everts PA, Devilee RJ, Brown Mahoney
C, et al: Exogenous application of
platelet-leukocyte gel during open
subacromial decompression contributes
to improved patient outcome: A
prospective randomized double-blind
study. Eur Surg Res 2008;40(2):203-210.
17. Bibbo C, Bono CM, Lin SS: Union rates
using autologous platelet concentrate
alone and with bone graft in high-risk
foot and ankle surgery patients. J Surg
Orthop Adv 2005;14(1):17-22.
18. Mei-Dan O, Carmont MR, Laver L,
Mann G, Maffulli N, Nyska M: Platelet-
rich plasma or hyaluronate in the
management of osteochondral lesions of
the talus. Am J Sports Med 2012;40(3):
534-541.
19. Mishra A, Pavelko T: Treatment of
chronic elbow tendinosis with buffered
platelet-rich plasma. Am J Sports Med
2006;34(11):1774-1778.
20. Silva A, Sampaio R: Anatomic ACL
reconstruction: Does the platelet-rich
plasma accelerate tendon healing? Knee
Surg Sports Traumatol Arthrosc 2009;
17(6):676-682.
21. Orrego M, Larrain C, Rosales J, et al:
Effects of platelet concentrate and a bone
plug on the healing of hamstring tendons
in a bone tunnel. Arthroscopy 2008;
24(12):1373-1380.
22. Rodeo SA, Delos D, Williams RJ, Adler
RS, Pearle A, Warren RF: The effect of
platelet-rich fibrin matrix on rotator cuff
tendon healing: A prospective,
randomized clinical study. Am J Sports
Med 2012;40(6):1234-1241.
23. Jo CH, Kim JE, Yoon KS, et al: Does
platelet-rich plasma accelerate recovery
after rotator cuff repair? A prospective
cohort study. Am J Sports Med 2011;
39(10):2082-2090.
24. Schepull T, Kvist J, Norrman H, Trinks
M, Berlin G, Aspenberg P: Autologous
platelets have no effect on the healing of
human achilles tendon ruptures: A
randomized single-blind study. Am J
Sports Med 2011;39(1):38-47.
25. Tsai CH, Hsu HC, Chen YJ, Lin MJ,
Chen HT: Using the growth factors-
enriched platelet glue in spinal fusion
and its efficiency. J Spinal Disord Tech
2009;22(4):246-250.
26. Carreon LY, Glassman SD, Anekstein Y,
Puno RM: Platelet gel (AGF) fails to
increase fusion rates in instrumented
posterolateral fusions. Spine (Phila Pa
1976) 2005;30(9):E243-E246, discussion
E247.
27. Weiner BK, Walker M: Efficacy of
autologous growth factors in lumbar
intertransverse fusions. Spine (Phila Pa
1976) 2003;28(17):1968-1970, discus-
sion 1971.
Wellington K. Hsu, MD, et al
28. Filardo G, Kon E, Della Villa S,
Vincentelli F, Fornasari PM, Marcacci
M: Use of platelet-rich plasma for the
treatment of refractory jumper’s knee.
Int Orthop 2010;34(6):909-915.
29. Radice F, Yánez R, Gutiérrez V, Rosales
J, Pinedo M, Coda S: Comparison of
magnetic resonance imaging findings in
anterior cruciate ligament grafts with
and without autologous platelet-derived
growth factors. Arthroscopy 2010;26(1):
50-57.
30. Sánchez M, Anitua E, Azofra J, Andía I,
Padilla S, Mujika I: Comparison of
surgically repaired Achilles tendon tears
using platelet-rich fibrin matrices. Am J
Sports Med 2007;35(2):245-251.
31. Marx RE: Platelet-rich plasma: Evidence
to support its use. J Oral Maxillofac
Surg 2004;62(4):489-496.
32. Tayapongsak P, O’Brien DA, Monteiro
CB, Arceo-Diaz LY: Autologous fibrin
adhesive in mandibular reconstruction
with particulate cancellous bone and
marrow. J Oral Maxillofac Surg 1994;
52(2):161-165, discussion 166.
33. Hall MP, Band PA, Meislin RJ, Jazrawi
LM, Cardone DA: Platelet-rich plasma:
Current concepts and application in
sports medicine. J Am Acad Orthop Surg
2009;17(10):602-608.
34. Mazzocca AD, McCarthy MB,
Chowaniec DM, et al: Platelet-rich
plasma differs according to preparation
method and human variability. J Bone
Joint Surg Am 2012;94(4):308-316.
35. DeLong JM, Russell RP, Mazzocca AD:
Platelet-rich plasma: The PAW
classification system. Arthroscopy 2012;
28(7):998-1009.
36. Wasterlain AS, Braun HJ, Harris AH,
Kim HJ, Dragoo JL: The systemic effects
of platelet-rich plasma injection. Am J
Sports Med 2013;41(1):186-193.
37. Harris SE, Bonewald LF, Harris MA,
et al: Effects of transforming growth
factor beta on bone nodule formation
and expression of bone morphogenetic
protein 2, osteocalcin, osteopontin,
alkaline phosphatase, and type I collagen
mRNA in long-term cultures of fetal rat
calvarial osteoblasts. J Bone Miner Res
1994;9(6):855-863.
38. Han B, Woodell-May J, Ponticiello M,
Yang Z, Nimni M: The effect of
thrombin activation of platelet-rich
plasma on demineralized bone matrix
osteoinductivity. J Bone Joint Surg Am
2009;91(6):1459-1470.
39. Castillo TN, Pouliot MA, Kim HJ,
Dragoo JL: Comparison of growth factor
and platelet concentration from
commercial platelet-rich plasma
separation systems. Am J Sports Med
2011;39(2):266-271.
747
Platelet-rich Plasma in Orthopaedic Applications: Evidence-based Recommendations for Treatment
40. Sundman EA, Cole BJ, Fortier LA:
Growth factor and catabolic cytokine
concentrations are influenced by the
cellular composition of platelet-rich
plasma. Am J Sports Med 2011;39(10):
2135-2140.
41. Metcalf KB, Mandelbaum BR,
McIlwraith CW: Application of platelet-
rich plasma to disorders of the knee
joint. Cartilage 2013;4(4):295-312.
42. Harvest Terumo: SmartPrep2: The
Optimal Platelet Rich Plasma
Composition. Available at: http://
www.harvesttech.com/pdf/SL-021-0961-
PRPCorporateBrochure.pdf. Accessed
October 3, 2013.
43. Fallouh L, Nakagawa K, Sasho T, et al:
Effects of autologous platelet-rich
plasma on cell viability and collagen
synthesis in injured human anterior
cruciate ligament. J Bone Joint Surg Am
2010;92(18):2909-2916.
44. Leitner GC, Koszik F, Rudnicki T, et al:
Apheresis products of the Amicus and
the AS.TEC 204 cell separators are
comparable with regard to dendritic cells
derived from the mononuclear cell
collection. Vox Sang 2007;92(1):37-41.
45. Mazzucco L, Balbo V, Cattana E,
Guaschino R, Borzini P: Not every PRP-
gel is born equal: Evaluation of growth
factor availability for tissues through
four PRP-gel preparations. Fibrinet,
RegenPRP-Kit, Plateltex and one manual
procedure. Vox Sang 2009;97(2):110-
118.
46. Weibrich G, Kleis WK, Hitzler WE,
Hafner G: Comparison of the platelet
concentrate collection system with the
plasma-rich-in-growth-factors kit to
produce platelet-rich plasma: A technical
report. Int J Oral Maxillofac Implants
2005;20(1):118-123.
47. Giusti I, Rughetti A, D’Ascenzo S, et al:
Identification of an optimal
concentration of platelet gel for
promoting angiogenesis in human
endothelial cells. Transfusion 2009;
49(4):771-778.
748
48. Mishra A, Harmon K, Woodall J, Vieira
A: Sports medicine applications of
platelet rich plasma. Curr Pharm
Biotechnol 2012;13(7):1185-1195.
49. Okamoto S, Ikeda T, Sawamura K, et al:
Positive effect on bone fusion by the
combination of platelet-rich plasma and
a gelatin β-tricalcium phosphate sponge:
A study using a posterolateral fusion
model of lumbar vertebrae in rats. Tissue
Eng Part A 2012;18(1-2):157-166.
50. Iqbal J, Pepkowitz SH, Klapper E:
Platelet-rich plasma for the
replenishment of bone. Curr Osteoporos
Rep 2011;9(4):258-263.
51. Leitner GC, Gruber R, Neumüller J,
et al: Platelet content and growth factor
release in platelet-rich plasma: A
comparison of four different systems.
Vox Sang 2006;91(2):135-139.
52. American Academy of Orthopaedic
Surgeons: Treatment of Osteoarthritis of
the Knee: Evidence-Based Guideline, 2nd
Edition. Available at: http://
www.aaos.org/research/guidelines/
TreatmentofOsteoarthritisoftheKnee
Guideline.pdf. Accessed October 3,
2013.
53. Pierce GF, Mustoe TA, Lingelbach J,
Masakowski VR, Gramates P, Deuel TF:
Transforming growth factor beta
reverses the glucocorticoid-induced
wound-healing deficit in rats: Possible
regulation in macrophages by platelet-
derived growth factor. Proc Natl Acad
Sci U S A 1989;86(7):2229-2233.
54. Marx RE: Platelet-rich plasma (PRP):
What is PRP and what is not PRP?
Implant Dent 2001;10(4):225-228.
55. Murray MM, Spindler KP, Ballard P,
Welch TP, Zurakowski D, Nanney LB:
Enhanced histologic repair in a central
wound in the anterior cruciate ligament
with a collagen-platelet-rich plasma
scaffold. J Orthop Res 2007;25(8):1007-
1017.
56. Sánchez M, Anitua E, Azofra J, Prado R,
Muruzabal F, Andia I: Ligamentization
of tendon grafts treated with an
Journal of the American Academy of Orthopaedic Surgeons
endogenous preparation rich in growth
factors: Gross morphology and histology.
Arthroscopy 2010;26(4):470-480.
57. Vavken P, Sadoghi P, Murray MM: The
effect of platelet concentrates on graft
maturation and graft-bone interface
healing in anterior cruciate ligament
reconstruction in human patients: A
systematic review of controlled trials.
Arthroscopy 2011;27(11):1573-1583.
58. Magnussen RA, Flanigan DC, Pedroza
AD, Heinlein KA, Kaeding CC: Platelet
rich plasma use in allograft ACL
reconstructions: Two-year clinical results
of a MOON cohort study. Knee 2013;
20(4):277-280.
59. Kartus J, Magnusson L, Stener S,
Brandsson S, Eriksson BI, Karlsson J:
Complications following arthroscopic
anterior cruciate ligament
reconstruction: A 2-5-year follow-up of
604 patients with special emphasis on
anterior knee pain. Knee Surg Sports
Traumatol Arthrosc 1999;7(1):2-8.
60. Visentini PJ, Khan KM, Cook JL, Kiss
ZS, Harcourt PR, Wark JD; Victorian
Institute of Sport Tendon Study Group:
The VISA score: An index of severity of
symptoms in patients with jumper’s knee
(patellar tendinosis). J Sci Med Sport
1998;1(1):22-28.
61. Chahal J, Van Thiel GS, Mall N, et al:
The role of platelet-rich plasma in
arthroscopic rotator cuff repair: A
systematic review with quantitative
synthesis. Arthroscopy 2012;28(11):
1718-1727.
62. GlobalData: Platelet Rich Plasma: A
Market Snapshot. Available at: http://
www.docstoc.com/docs/47503668/
Platelet-Rich-Plasma-A-Market-
Snapshot. Accessed September 17, 2013.
63. Dougherty EJ: An evidence-based model
comparing the cost-effectiveness of
platelet-rich plasma gel to alternative
therapies for patients with nonhealing
diabetic foot ulcers. Adv Skin Wound
Care 2008;21(12):568-575.